Step 1: Synthesis of Intermediate 2
To a suspension of (S)-proline (11.4 g, 99 mmol) and chloral hydrate (35 g, 211.6 mmol) in MeCN (100 mL), MgSO4 (30 g) was added. The mixture was heated at 60 °C for 24 hours, then stirred at room temperature for 2 days, and then filtered. The residue was washed with EtOAc, and the combined organic phases were concentrated. The residue was dissolved in EtOAc, and the resulting solution was washed with a saturated NaHCO3 aqueous solution, dried over MgSO4, and concentrated.
The crude product was recrystallized from EtOH to give oxazolidinone 2 (10.2 g, 40%) as a white solid. Step 2: Synthesis of Intermediate 3 At -78°C, an ice-cold solution of 2 M LDA (2.6 mL, 5.20 mmol) was added dropwise to a THF (30 mL) solution of oxazolidinone 2 (1.05 g, 4.30 mmol). After 30 minutes, MeI (0.54 mL, 8.67 mmol) was added dropwise, and the mixture was warmed to -30°C over 2 hours. Water was added before warming the mixture to RT. The mixture was extracted with CHCl3, the combined extracts were washed with brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (eluting with 0 to 100% EtOAc in petroleum ether) to give oxazolidinone 3 (430 mg, 39%) as a pale yellow oil. Step 3: Synthesis of (S)-2-Methylpyrrolidine-2-carboxylic acid hydrochloride (4) Oxazolidinone 3 (430 mg, 1.66 mmol) was added to 6 M HCl (5 mL) and heated to reflux for 3 hours. The mixture was concentrated, and the residue was then ground with hot acetone. After cooling and standing (24 hours), the acetone was poured off, and the residue was dried, leaving the HCl salt as a white solid (160 mg). ¹H NMR (500 MHz, D₂O) Δδ 3.47–3.36 (m, 1H), 2.43–2.35 (m, 1H), 2.17–1.94 (m, 3H), 1.64 (s, 3H). Crude compound 4 was dissolved in MeOH and passed through an Amberlyst A21 resin column (eluted with water) to give a white solid in zwitterionic form (81 mg, 38%).
